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Red walnut has broad market prospects because it is richer in anthocyanins than ordinary walnut. However, the mechanism driving anthocyanin biosynthesis in red walnut is still unknown. We studied two types of red walnut, called red walnut 1 (R1), with a red pericarp and seed coat, and red walnut 2 (R2), with a red seed coat only. R1 mostly contained cyanidin-3-O-galactoside, while R2 contained a various amounts of cyanidin-3-O-galactoside, cyanidin-3-O-arabinoside, and cyanidin-3-O-glucoside. The LDOX-2 (LOC109007163) and LDOX-3 (LOC109010746) genes, which encode leucoanthocyanidin dioxygenase/anthocyanidin synthase (LDOX/ANS), were preliminarily indicated as the crucial genes for anthocyanin biosynthesis in R1 and R2, respectively. The MYB differential genes analysis showed that MYB27 and MYB113 are specifically expressed in the red parts of R1 and R2, respectively, and they are regarded as candidate regulatory genes. Ectopic expression in Arabidopsis and transient injection in walnut showed that both MYB27 and MYB113 were located in the nucleus and promoted anthocyanin accumulation, while MYB27 promoted the expression of LDOX-2, and MYB113 promoted the expression of LDOX-3 and UAGT-3. Yeast one-hybrid and electrophoretic mobility shift assays showed that MYB27 could only bind to the LDOX-2 promoter, while MYB113 could bind to the promoters of both LDOX-3 and UAGT-3. In addition, we also identified an HD-Zip transcription factor, ATHB-12, which is specifically expressed in the pericarp. After silencing the expression of ATHB-12, the R2 pericarp turned red, and MYB113 expression increased. Further experiments showed that ATHB-12 could specifically interact with MYB113 and bind to its promoter. This suggests that MYB27 controls R1 coloration by regulating LDOX-2, while MYB113 controls R2 coloration by regulating LDOX-3 and UAGT-3, but ATHB-12 can specifically bind to and inhibit the MYB113 of the R2 pericarp so that it becomes unpigmented. This study reveals the anthocyanin biosynthetic mechanisms in two different types of red walnut and provides a scientific basis for the selection and breeding of red walnut varieties.

Abstract. Background:. We previously reported that activation of the cell cycle in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enhances their remuscularization capacity after human cardiac muscle patch transplantation in infarcted mouse hearts. Herein, we sought to identify the effect of magnesium lithospermate B (MLB) on hiPSC-CMs during myocardial repair using a myocardial infarction (MI) mouse model. Methods:. In C57BL/6 mice, MI was surgically induced by ligating the left anterior descending coronary artery. The mice were randomly divided into five groups (n = 10 per group); a MI group (treated with phosphate-buffered saline only), a hiPSC-CMs group, a MLB group, a hiPSC-CMs + MLB group, and a Sham operation group. Cardiac function and MLB therapeutic efficacy were evaluated by echocardiography and histochemical staining 4 weeks after surgery. To identify the associated mechanism, nuclear factor (NF)-κB p65 and intercellular cell adhesion molecule-1 (ICAM1) signals, cell adhesion ability, generation of reactive oxygen species, and rates of apoptosis were detected in human umbilical vein endothelial cells (HUVECs) and hiPSC-CMs. Results:. After 4 weeks of transplantation, the number of cells that engrafted in the hiPSC-CMs + MLB group was about five times higher than those in the hiPSC-CMs group. Additionally, MLB treatment significantly reduced tohoku hospital pediatrics-1 (THP-1) cell adhesion, ICAM1 expression, NF-κB nuclear translocation, reactive oxygen species production, NF-κB p65 phosphorylation, and cell apoptosis in HUVECs cultured under hypoxia. Similarly, treatment with MLB significantly inhibited the apoptosis of hiPSC-CMs via enhancing signal transducer and activator of transcription 3 (STAT3) phosphorylation and B-cell lymphoma-2 (BCL2) expression, promoting STAT3 nuclear translocation, and downregulating BCL2-Associated X, dual specificity phosphatase 2 (DUSP2), and cleaved-caspase-3 expression under hypoxia. Furthermore, MLB significantly suppressed the production of malondialdehyde and lactate dehydrogenase and the reduction in glutathione content induced by hypoxia in both HUVECs and hiPSC-CMs in vitro. Conclusions:. MLB significantly enhanced the potential of hiPSC-CMs in repairing injured myocardium by improving endothelial cell function via the NF-κB/ICAM1 pathway and inhibiting hiPSC-CMs apoptosis via the DUSP2/STAT3 pathway.

Abstract Calcific aortic valve disease (CAVD) and osteoarthritis (OA) are common diseases in the ageing population and share similar pathogenesis, especially in inflammation. This study aims to discover potential diagnostic and therapeutic targets in patients with CAVD and OA. Three CAVD datasets and one OA dataset were obtained from the Gene Expression Omnibus database. We used bioinformatics methods to search for key genes and immune infiltration, and established a ceRNA network. Immunohistochemical staining was performed to verify the expression of candidate genes in human and mice aortic valve tissues. Two key genes obtained, leucine rich repeat containing 15 (LRRC15) and secreted phosphoprotein 1 (SPP1), were further screened using machine learning and verified in human and mice aortic valve tissues. Compared to normal tissues, the infiltration of immune cells in CAVD tissues was significantly higher, and the expressions of LRRC15 and SPP1 were positively correlated with immune cells infiltration. Moreover, the ceRNA network showed extensive regulatory interactions based on LRRC15 and SPP1. The authors’ findings identified LRRC15 and SPP1 as hub genes in immunological mechanisms during CAVD and OA initiation and progression, as well as potential targets for drug development.

Even though N6-methyladenosine (m6A) RNA modifications are increasingly being implicated in human disease, their mechanisms are not fully understood in smokers with coronary artery disease (CAD). Thirty m6A-related regulators’ expression (MRRE) in CAD individuals (smokers and non-smokers) were analyzed from GEO. Support Vector Machine, random forest, and nomogram models were constructed to assess its clinical value. Consensus clustering, principal component analysis, and ssGSEA were used to construct a full picture of m6A-related regulators in smokers with CAD. Oxygen-glucose deprivation (OGD) and qRT-PCR were used to validate hypoxia’s effect on MRRE. A comparison between smokers with CAD and controls revealed lower expression levels of RBM15B, YTHDC2, and ZC3H13. Based on three key MRREs, all models showed good clinical value, and smokers with CAD were divided into two distinct molecular subgroups. The correlations were found between key MRRE and the degree of immune infiltration. Three key MRREs in HUVECs and FMC84 mouse cardiomyocytes were reduced in the OGD group. Through hypoxia, smoking might reduce the expression levels of RBM15B, YTHDC2, and ZC3H13 in smokers with CAD. Our findings provide an important theoretical basis for the treatment of smokers with CAD.

Abstract Patient‐Derived Organoids (PDO) and Xenografts (PDX) are the current gold standards for patient‐derived models of cancer (PDMC). Nevertheless, how patient tumor cells evolve in these models and the impact on drug response remains unclear. Herein, the transcriptomic and chromatin accessibility landscapes of matched colorectal cancer (CRC) PDO, PDX, PDO‐derived PDX (PDOX), and original patient tumors (PT) are compared. Two major remodeling axes are discovered. The first axis delineates PDMC from PT, and the second axis distinguishes PDX and PDO. PDOX are more similar to PDX than PDO, indicating the growth environment is a driving force for chromatin adaptation. Transcription factors (TF) that differentially bind to open chromatins between matched PDO and PDOX are identified. Among them, KLF14 and EGR2 footprints are enriched in PDOX relative to matched PDO, and silencing of KLF14 or EGR2 promoted tumor growth. Furthermore, EPHA4, a shared downstream target gene of KLF14 and EGR2, altered tumor sensitivity to MEK inhibitor treatment. Altogether, patient‐derived CRC cells undergo both common and distinct chromatin remodeling in PDO and PDX/PDOX, driven largely by their respective microenvironments, which results in differences in growth and drug sensitivity and needs to be taken into consideration when interpreting their ability to predict clinical outcome.

Abstract The essential branched‐chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs’ full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence‐associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation‐related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age‐related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age‐related and inflammatory diseases.

Percutaneous closure has emerged as the standard treatment for secundum-type atrial septal defects (ASDs). However, there is a rare but serious complication of occluder device migration and embolization to the heart chambers or distal vasculature during or shortly after implantation. Although this occurrence is extremely rare, it can have disastrous consequences. Fortunately, advancements in equipment and technology have facilitated the transition from surgical procedures to percutaneous techniques for removing embolized occluder devices. In this report, we present a case in which an Amplatzer septal occluder (ASO) device embolized to the descending thoracic aortic isthmus two days after implantation. The device was successfully retrieved using a percutaneous technique, and another ASO device was subsequently redeployed to the ASD. Regrettably, the patient experienced an intraoperative cardiac arrest. Despite prompt rescue efforts and recovery of vital signs, the patient still suffered postoperative sequelae. The main reason for occluder device migration in this case may have been the undersizing of the ASO device due to the operator's lack of caution.

Congenital coronary artery fistula (CAF) represents a remarkable rarity within the realm of cardiovascular anomalies, characterized by an aberrant connection between coronary arteries and either cardiac chambers or major vessels. Clinical manifestations of CAFs often remain unspecified or may even be entirely absent, posing diagnostic challenges. Notably, patients harboring substantial CAFs may exhibit symptoms such as palpitations, chest tightness, and dyspnea. Although right-sided congenital CAFs are relatively prevalent, the occurrence of a CAF accompanied by a colossal pseudoaneurysm imposing compression upon the pulmonary vein is an exceedingly rare phenomenon. This exceptional case report delineates a singular fistula originating from the right coronary artery, extending its course to the right atrium, and remarkably featuring a substantial pseudoaneurysm exerting compression upon the right superior pulmonary vein. Therapeutic intervention encompassed surgical closure of the proximal artery and excision of the pseudoaneurysm, underscoring the complexity and criticality of managing such intricate cardiac anomalies to ensure optimal patient outcomes.

One of the major bottlenecks in advancing basic cancer research and developing novel cancer therapies is the lack of in vitro pre-clinical models that faithfully recapitulate tumor properties in the patients. Monolayer cultures of cancer cell lines usually lose the heterogeneity of the parental tumors, while patient-derived xenograft (PDX) suffers from its time- and resource-intensive nature. The emergence of organoid culture system and its application in cancer research provides a unique opportunity to develop novel in vitro cancer pre-clinical models. Here we review the recent advances in utilizing organoids culture system and other related three-dimensional culture systems in studying cancer biology, performing drug screening, and developing cancer therapies. In particular, we discuss the advantages of applying xenograft initiated from patient-derived organoids (PDOs) as a faithful cancer pre-clinical model in basic cancer research and precision medicine.

BackgroundRecent observational studies and meta-analyses have shown that vitamin C reduces cancer incidence and mortality, but the underlying mechanisms remain unclear. We conducted a comprehensive pan-cancer analysis and biological validation in clinical samples and animal tumor xenografts to understand its prognostic value and association with immune characteristics in various cancers.MethodsWe used the Cancer Genome Atlas gene expression data involving 5769 patients and 20 cancer types. Vitamin C index (VCI) was calculated using the expression of 11 genes known to genetically predict vitamin C levels, which were classified into high and low subgroups. The correlation between VCI and patient overall survival (OS), tumor mutational burden (TMB), microsatellite instability (MSI), and immune microenvironment was evaluated, using Kaplan-Meier analysis method and ESTIMATE (https://bioinformatics.mdanderson.org/estimate/). Clinical samples of breast cancer and normal tissues were used to validate the expression of VCI-related genes, and animal experiments were conducted to test the impact of vitamin C on colon cancer growth and immune cell infiltration.ResultsSignificant changes in expression of VCI-predicted genes were observed in multiple cancer types, especially in breast cancer. There was a correlation of VCI with prognosis in all samples (adjusted hazard ratio [AHR] = 0.87; 95% confidence interval [CI] = 0.78–0.98; P = 0.02). The specific cancer types that exhibited significant correlation between VCI and OS included breast cancer (AHR = 0.14; 95% CI = 0.05–0.40; P < 0.01), head and neck squamous cell carcinoma (AHR = 0.20; 95% CI = 0.07–0.59; P < 0.01), kidney clear cell carcinoma (AHR = 0.66; 95% CI = 0.48–0.92; P = 0.01), and rectum adenocarcinoma (AHR = 0.01; 95% CI = 0.001–0.38; P = 0.02). Interestingly, VCI was correlated with altered immunotypes and associated with TMB and MSI negatively in colon and rectal adenocarcinoma (P < 0.001) but positively in lung squamous cell carcinoma (P < 0.05). In vivo study using mice bearing colon cancer xenografts demonstrated that vitamin C could inhibit tumor growth with significant impact on immune cell infiltration.ConclusionVCI is significantly correlated with OS and immunotypes in multiple cancers, and vitamin C might have therapeutic potential in colon cancer.

Climate change (CC) has become a central global topic within the multiple branches of social disciplines. Natural Language Processing (NLP) plays a superior role since it has achieved marvelous accomplishments in various application scenarios. However, CC debates are ambiguous and complicated to interpret even for humans, especially when it comes to the aspect-oriented fine-grained level. Furthermore, the lack of large-scale effective labeled datasets is always a plight encountered in NLP. In this work, we propose a novel weak-supervised Hybrid Attention Masking Capsule Neural Network (HAMCap) for fine-grained CC debate analysis. Specifically, we use vectors with allocated different weights instead of scalars, and a hybrid attention mechanism is designed in order to better capture and represent information. By randomly masking with a Partial Context Mask (PCM) mechanism, we can better construct the internal relationship between the aspects and entities and easily obtain a large-scale generated dataset. Considering the uniqueness of linguistics, we propose a Reinforcement Learning-based Generator-Selector mechanism to automatically update and select data that are beneficial to model training. Empirical results indicate that our proposed ensemble model outperforms baselines on downstream tasks with a maximum of 50.08% on accuracy and 49.48% on F1 scores. Finally, we draw interpretable conclusions about the climate change debate, which is a widespread global concern.

There are limited cases of heart-lung transplantation (HLT) in children worldwide owing to lack of donors, demanding surgical teamwork, and arduous post-operative management. Post-transplant management difficulties stem from the possible development of several post-operative complications, with infection being a common complication. Intracranial fungal infections are difficult to diagnose and prone to treatment delays because of their relatively insidious onset and atypical clinical presentation. Here, we present a case of a cerebral infection developed 3 months after HLT in a 10-year-old child, showing no positive results on conventional imaging or cerebrospinal fluid (CSF) examination and culture. On metagenomic next-generation sequencing of the cerebrospinal fluid, the causative organism was finally determined as Aspergillus. After administering 1-year anti-Aspergillus treatment, no recurrence of intracranial fungal infection was noted during the 3-year follow-up. This case illustrates the multifaceted diagnostic techniques for cerebral aspergillosis after HLT and shows the significance of dynamic monitoring of symptoms, such as headache, and of metagenomic sequencing results, trends in intracranial pressure and (1-3)-β-D-glucan levels for guiding diagnosis and treatment.

Syn-subduction basins bear significant implications to understand tectonic evolution of any fossil subduction zone. The late Paleozoic to early Mesozoic (Paleo-Tethyan) tectonics of the eastern and southeastern Tibetan Plateau (i.e., the Sanjiang Orogenic Belt) is featured by ocean-continent subduction systems. A huge pile of volcanic-absent sedimentary succession developed in the middle segment of the Sanjiang orogenic belt, its age and tectonic nature remain unclear. Detailed geological mapping and zircon U-Pb dating results demonstrate that the early Late Triassic volcanic-absent succession comprises the nonmarine Maichuqing Formation in the lower part and the shallow marine Sanhedong Formation in the upper part. The Maichuqing Formation consists of coarse to fine-grained sandstone, siltstone and mudstone with abundant basal erosional surfaces, trough and planar cross-beddings, ripples, mudcracks, and plant fragments. The Sanhedong Formation comprises predominantly bioclastic limestones interlayered with marl, calcareous-muddy siltstone, and calcareous sandstone with abundant bivalve fossils. Syn-sedimentation deformation structures, such as slump folds and associated normal faults are common, suggesting intense tectonism during deposition. Synthesizing sedimentary data, paleocurrent and provenance results, combined with other available data, demonstrate that the volcanic-absent succession deposited within a retro-foreland basin along the rear part of the Permian-Triassic Jomda-Weixi-Yunxian arc in response to flat-subduction of the Paleo-Tethyan Ocean during the early Late Triassic time.

Percutaneous closure of atrial septal defect (ASD) has emerged as a feasible alternative strategy to surgical repair in many cardiac centers worldwide. Occluder recanalization due to device failure is a rare and severe complication that often occurs within weeks to years after ASD closure. We reported a rare ultra-long-term complication of occluder recanalization due to delayed spontaneous perforation of polyvinyl alcohol (PVA) membrane of ASD occluder after 18 years of ASD closure. Surgical removal of the faulty device and reconstruction of the atrial septum with a bovine pericardial patch was performed. The patient was discharged and recovered uneventfully without syncope or residual shunt. The cause of this rare complication of spontaneous PVA membrane perforation of the occluder has not been fully detected. To our knowledge, this is the first report about PVA membrane perforation of an occluder that occurred soon after ASD closure.

This study investigated the impact of a multiple epoxy chain extender (ADR) on the rheological behavior, crystallization, and mechanical properties of polyglycolic acid (PGA). Tests of the torque and melt mass flow rate and dynamic rheological analysis were conducted to study the rheological behavior of PGA modified with ADR. The rheological results of the modified PGA showed a significantly increased viscosity and storage modulus with an increase in the ADR amount, which could be attributed to the chain extension/branching reactions between PGA and ADR. It was proved that ADR could be used as an efficient chain extender for tailoring the rheological performance of PGA. The Han plot of the modified PGA showed a transition of viscous behavior to elastic behavior, while the ADR content was increased from 0 to 0.9 phr. The formation of long-chain branches (LCBs) was confirmed via the Cole–Cole plot and weighted relaxation spectrum, wherein the LCBs substantially changed the rheological behavior of the modified PGA. The vGP plots predicted a star-type topological structure for the LCBs. The results of non-isothermal crystallization kinetics suggested that the crystallization of the modified PGA was predominantly homogeneous nucleation and three-dimensional growth. The crystallinity decreased slightly with the increase in the ADR amount. Compared to neat PGA, the modified PGA samples exhibited better tensile and flexural performances.

Natural-language processing is well positioned to help stakeholders study the dynamics of ambiguous Climate Change-related (CC) information. Recently, deep neural networks have achieved good results on a variety of NLP tasks depending on high-quality training data and complex and exquisite frameworks. This raises two dilemmas: (1) the networks are highly reliant on powerful hardware devices and processing is time-consuming, which is not only inconducive to execution on edge devices but also leads to resource consumption. (2) Obtaining large-scale effective annotated data is difficult and laborious, especially when it comes to a special domain such as CC. In this paper, we propose a CC-domain-adapted BERT distillation and reinforcement ensemble (DARE) model for tackling the problems above. Specifically, we propose a novel data-augmentation strategy which is a Generator-Reinforced Selector collaboration network for countering the dilemma of CC-related data scarcity. Extensive experimental results demonstrate that our proposed method outperforms baselines with a maximum of 26.83% on SoTA and 50.65× inference time speed-up. Furthermore, as a remedy for the lack of CC-related analysis in the NLP community, we also provide some interpretable conclusions for this global concern.

Cell based materials production has potential for generating diverse materials with a range of functions. Here, the authors report development of living fabrication of biohybrid semi interpenetrating polymer networks by encapsulating protein producing bacteria within polymer microcapsules.

AimsThe study explores the leading causes of postoperative extubation difficulties in pediatric patients (neonates and toddlers) with congenital heart diseases and establishes individualized treatment for different reasons.MethodWe retrospectively analyzed medical records of 4,971 pediatric patients with congenital heart defects treated in three tertiary Congenital Heart Disease Centres in China from January 2005 to December 2020, from whom we selected those with difficulty extubation but successful weaning during the postoperative period. Next, we performed an analysis of risk factors and reported the combined experience of individualized treatment for successful extubation.ResultsSeventy-five pediatric patients were identified in our database, among whom 23 had airway stenosis, 17 had diaphragmatic dysfunction, and 35 had pulmonary infection. The patients were all successfully weaned from the ventilator after an individualized treatment plan. In addition, the intubation time in the airway stenosis group was 17.7 ± 9.0, 33.6 ± 13.9 days in the diaphragmatic dysfunction group, and 11.9 ± 3.8 days in the pulmonary infection group.ConclusionGiven the primary reasons for difficult weaning following open-heart surgery in pediatric patients with congenital heart diseases, an individualized treatment scheme can achieve the ideal therapeutic effect where patients can be weaned faster with a shorter intubation period.

In this paper, a method for medical image registration based on the bounded generalized Gaussian mixture model is proposed. The bounded generalized Gaussian mixture model is used to approach the joint intensity of source medical images. The mixture model is formulated based on a maximum likelihood framework, and is solved by an expectation-maximization algorithm. The registration performance of the proposed approach on different medical images is verified through extensive computer simulations. Empirical findings confirm that the proposed approach is significantly better than other conventional ones.

With regards to the Sinicization of Christianity (基督教中國化), there has always been a tension between “Chinese Christians” (中國(人)基督徒) and “Christian Chinese” (基督徒中國人). This paper intends to respond to this tension through the analysis of The Jesus Family (耶穌家庭), an important representative of the indigenous church movement in modern China. The Jesus Family had its own unique theological propositions and ecclesial practices. Particularly noteworthy was its emphasis on the living community of believers. Below, we present research on The Jesus Family, analyzed from two distinct aspects: those of “Jesus” and “family”. If the return to “Jesus” reflected the movement’s restorationist theological position, the “family” can be seen as reflecting the movement’s sociological advocacy for the practice of communitarian Christian principles. We argue that these aspects of The Jesus Family—emphasizing the values of personal intimacy with Jesus alongside communitarian principles—were key to its flourishing precisely within the unique context of modern Chinese social turmoil and history. In this light, The Jesus Family—both in its theological and sociological dimension—eludes simple classification as the product of “Chinese traditions” or “Christian orthodoxy.” Rather, it appears as the product of the interaction between the two, and we argue that in this, one sees also how the process of the Sinicization of Christianity relies on both traditional Chinese culture and Christian orthodoxy as inseparable and playing mutually interdependent roles.

Objective: We report a rare mutation on the α2-globin gene, HBA2: c.91_93delGAG and its potential functions. Case Report: We mainly described four patients with hemoglobin (Hb) H disease caused by the rare mutation and the SEA deletion but diversity in clinical presentation. Two had survived to adulthood with normal physical and mental development, except for mild anemia. However, two were children, who had more severe clinical manifestations. One child had developmental disorders of speech and language and mild growth retardation, and the other child suffered from severe hemolytic crises precipitated by infection and received blood transfusion. Conclusion: This study is of great significance for clinicians to provide genetic counseling to couples at-risk of having offspring with Hb H disease and let them make the pregnancy decision, particularly reduce the occurrence of severe Hb H disease.

Mounting evidence indicates that gut microbiome may be involved in the pathogenesis of type 2 diabetes mellitus (T2DM). However, there is no consensus on whether there is a causal link between gut microbiome and T2DM risk. In the present study, the Mendelian randomization (MR) analysis was performed to investigate whether gut microbiome was causally linked to T2DM risk. The single nucleotide polymorphisms (SNPs) that were significantly related to exposure from published available genome-wide association study (GWAS) were selected as instrumental variables (IVs). The robust methods including inverse variance weighting (IVW), MR Egger, and weighted median were conducted to infer the causal links. Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were used to test whether there was horizontal pleiotropy and identify outlier SNPs. The estimates of IVW suggested that Streptococcaceae (odds ratio (OR) = 1.17, 95% confidence interval (CI), 1.04–1.31, p = 0.009) was associated with higher risk of T2DM in European population. In Asian population, the MR IVW estimates revealed that there was a causal link between Acidaminococcaceae and T2DM risk (OR = 1.17, 95% CI, 1.04–1.31, p = 0.008). There was no evidence of notable heterogeneity and horizontal pleiotropy. However, after false discovery rate (FDR) correction, the causal link between gut microbiome and T2DM was absent (FDR, p > 0.05). In summary, using genetic instruments, this study does not find evidence of association between the 28 gut microbiome families and T2DM risk. However, Streptococcaceae and Acidaminococcaceae may have a borderline positive correlation with T2DM risk.

BackgroundAccumulating evidence has demonstrated the associations of omega-3 or omega-6 polyunsaturated fatty acids (PUFAs) with the disease activity and inflammatory mediators of systemic lupus erythematosus (SLE), but the evidence of causal links of omega-3 or omega-6 PUFAs on the risk for SLE remains inconclusive.ObjectivesThis study was conducted to evaluate the causal relationships between omega-3/omega-6 PUFAs and SLE by performing the Mendelian randomization (MR) analysis.MethodsGenome-wide significant single-nucleotide polymorphisms (SNPs) were obtained from genome-wide association studies (GWASs) of circulating omega-3/omega-6 levels (n = up to 13,544) and GWAS meta-analyses of SLE (n = 14,267), respectively. The bidirectional two-sample MR (TSMR) analysis was conducted to infer the causality.ResultsThe inverse-variance weighted (IVW) method revealed that genetically determined per SD increase in omega-3 levels were causally associated with an increased risk for SLE (odds ratios [ORs] = 1.49, 95% CI: 1.07, 2.08, p = 0.021), but no causal effect of omega-6 on the risk SLE was observed (IVW OR = 1.06, 95% CI: 0.72, 1.57, p = 0.759). In addition, there were no significantly causal associations in genetic predisposition to SLE with the changes of omega-3 and omega-6 levels, respectively (IVW beta for omega-3: 0.007, 95% CI: −0.006, 0.022, p = 0.299; IVW beta for omega-6: −0.008, 95% CI: −0.023, 0.006, p = 0.255).ConclusionThe present study revealed the possible causal role of omega-3 on increasing the risk for SLE, it could be the potential implications for dietary recommendations.

Sweet chestnut (Castanea sativa) is an endemic species of genus Castanea in Europe, which is widespread in the southern part of continental Europe. The complete genome sequence of chloroplast was determined through Illumina NovaSeq platform. Totally the genome of chloroplast was 160,938 bp in length, GC rich (36.8%), comprising a pair of 25,726 bp inverted repeat sequences, separated by a 90,519 bp large and 18,967 bp small single-copy regions. There were 129 genes, including 37 transfer RNA genes, 8 ribosomal RNA genes, and 84 protein-coding genes. The phylogenetic tree analysis showed that C. sativa exhibited the closest relationship with Castanea henryi.

Objective: We investigated the potency of cardiac repair based on echocardiography-guided multiple percutaneous left ventricular intramyocardial injection of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) after myocardial infarction (MI).Methods: Mice with surgically induced MI were randomly divided into three groups (n = 8 in each group) and subjected to echocardiography-guided percutaneous left ventricular infarcted border injection of hiPSC-CMs (single dose; 10 μl 3 × 105 cells) or repeated injections of hiPSC-CMs at post-MI weeks 1 and 2 (multiple doses). The sham group of animals underwent all surgical procedures necessary for MI induction except for ligation. Then 4 weeks after MI, heart function was measured with transthoracic echocardiography. Engraftment was evaluated through the detection of human-specific cardiac troponin T. Infarct size and collagen volume were calculated with Sirius Red/Fast Green staining. Angiogenesis was evaluated with isolectin B4 staining. Cardiac remodeling was evaluated from the cardiomyocyte minimal fiber diameter in the infarcted border zone. Apoptosis was detected via TdT-mediated dUTP Nick-End Labeling (TUNEL) staining in cardiomyocytes from the infarcted border zone.Results: No mice died after echocardiography-guided percutaneous left ventricular intramyocardial injection. hiPSC-CMs were about nine-fold higher in the multiple-dose group at week 4 compared to the single-dose group. Multiple-dose transplantation was associated with significant improvement in left ventricular function, infarct size, angiogenesis, cardiac remodeling, and cardiomyocyte apoptosis.Conclusion: Echocardiography-guided multiple percutaneous left ventricular intramyocardial injection is a feasible, satisfactory, repeatable, relatively less invasive, and effective method of delivering cell therapy. The delivery of hiPSC-CMs indicates a novel therapy for MI.

Objective: The study aims to establish a new method in the Tetralogy of Fallot (ToF) called the pulmonary valve bi-orifice method (pulmonary annular sparing with an individualized autologous pericardial patch; thus, two orifices are formed at the level of the pulmonary valve annulus) to reconstruct the right ventricular outflow tract (RVOT).Methods: A retrospective analysis of 128 TOF patients from October 2009 to June 2018 with severe pulmonary valve dysplasia who underwent transvalvular annular patch (TAP) procedure (control group) or an individualized pulmonary valve bi-orifice procedure (observation group) were studied. The RVOT for each patient in the observation group was individually reconstructed per the patient's weight and the size of the autologous pulmonary valve using the bi-orifice method; however, increasing the cross-sectional area of the pulmonary valve annulus without destroying its integrity. The result was then compared to the control group, where TAP procedures were applied to evaluate the short to mid-term outcome(s). An in vitro simulation test was used to verify the anti-regurgitation mechanism of the new method.Results: The in vitro simulation test indicated that the anti-regurgitation mechanism was completed by the pericardial patch and the autologous pulmonary valve movement toward each other. Thus, for clinical applications, patients in both groups were compared. The results showed no significant differences in cardiopulmonary bypass and aortic cross-clamp time, mechanical ventilation, and ICU and post-operative residence between the two groups.During the follow-up period (3- to 12-years), 14 patients in the observation group had mild regurgitation after surgery (22.2%), while 10 patients had moderate pulmonary regurgitation (15.8%) with no right ventricular (RV) dilation. On the other hand, 22 patients (39.6%) had moderate to severe regurgitation in the control group, while left pulmonary artery stenosis occurred in one patient. In the control group, six patients (9.2%) with severe RV dilation were reoperated.Conclusion: Individualized pulmonary valve bi-orifice procedure is a safe and excellent method for reconstructing RVOT in ToF.

Abstract Colorectal cancer (CRC) metastasizes mainly to the liver, which accounts for the majority of CRC‐related deaths. Here it is shown that metastatic cells undergo specific chromatin remodeling in the liver. Hepatic growth factor (HGF) induces phosphorylation of PU.1, a pioneer factor, which in turn binds and opens chromatin regions of downstream effector genes. PU.1 increases histone acetylation at the DPP4 locus. Precise epigenetic silencing by CRISPR/dCas9KRAB or CRISPR/dCas9HDAC revealed that individual PU.1‐remodeled regulatory elements collectively modulate DPP4 expression and liver metastasis growth. Genetic silencing or pharmacological inhibition of each factor along this chromatin remodeling axis strongly suppressed liver metastasis. Therefore, microenvironment‐induced epimutation is an important mechanism for metastatic tumor cells to grow in their new niche. This study presents a potential strategy to target chromatin remodeling in metastatic cancer and the promise of repurposing drugs to treat metastasis.

The aluminum foam sandwich (AFS), which perfectly combines the excellent merits of an aluminum foam core and face sheet materials, has extensive and reliable applications in many fields, such as aerospace, military equipment, transportation, and so on. Adhesive bonding is one of the most widely used methods to produce AFS due to its general applicability, simple process, and low cost, however, the bonding interface is known as the weak link and may cause a serious accident. To overcome the shortcomings of a bonded AFS interface, short carbon fiber as a reinforcement phase was introduced to epoxy resin to reinforce the interface adhesion strength of AFS. Single lap shear tests and three-point bending tests were conducted to study the mechanical behavior of the reinforced interface and AFS, respectively. The failure mechanism was studied through a macro- and microanalysis. The result showed that after the reinforcement of carbon fiber, the tangential shear strength of the interface increased by 73.65%. The effective displacement of AFS prepared by the reinforced epoxy resin is 125.95% more than the AFS prepared by the unreinforced epoxy resin. The flexure behavior of the reinforced AFS can be compared with AFS made through a metallurgical method. Three categories of reinforcement mechanisms were discovered: (a) the pull off and pull mechanism: when the modified carbon fiber performed as the bridge, the bonding strength improved because of the pull off and pull out of fibers; (b) adhesion effect: the carbon fiber gathered in the hole edge resulted in epoxy resins being gathered in there too, which increased the effective bonding area of the interface; (c) mechanical self-locking effect: the carbon fiber enhanced the adhesive filling performance of aluminum foam holes, which improved the mechanical self-locking effect of the bonding interface.

The observational association between gut microbiome and systemic lupus erythematosus (SLE) has been well documented. However, whether the association is causal remains unclear. The present study used publicly available genome-wide association study (GWAS) summary data to perform two-sample Mendelian randomization (MR), aiming to examine the causal links between gut microbiome and SLE. Two sets of MR analyses were conducted. A group of single nucleotide polymorphisms (SNPs) that less than the genome-wide statistical significance threshold (5 × 10-8) served as instrumental variables. To obtain a comprehensive conclusion, the other group where SNPs were smaller than the locus-wide significance level (1 × 10-5) were selected as instrumental variables. Based on the locus-wide significance level, the results indicated that there were causal effects of gut microbiome components on SLE risk. The inverse variance weighted (IVW) method suggested that Bacilli and Lactobacillales were positively correlated with the risk of SLE and Bacillales, Coprobacter and Lachnospira were negatively correlated with SLE risk. The results of weighted median method supported that Bacilli, Lactobacillales, and Eggerthella were risk factors for SLE and Bacillales and Coprobacter served as protective factors for SLE. The estimates of MR Egger suggested that genetically predicted Ruminiclostridium6 was negatively associated with SLE. Based on the genome-wide statistical significance threshold, the results showed that Actinobacteria might reduce the SLE risk. However, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) detected significant horizontal pleiotropy between the instrumental variables of Ruminiclostridium6 and outcome. This study support that there are beneficial or detrimental causal effects of gut microbiome components on SLE risk.

Apple replant disease (ARD) is a common soil disease that occurs in apple-growing areas around the world, causing root tip rot and necrosis, plant growth retardation and even plant death. Biofumigation is a promising strategy for controlling ARD due to its advantages of convenient application and being environmentally friendly. Tagetes erecta is an effective biological fumigant, but its effect on ARD is unclear. In the present study, we used Malus hupehensis Rehd. seedlings as the test material to detect the mitigating effects of different forms of T. erecta: air-dried sample (DS), fresh samples (FS) and fresh sample infusion solution (IS) on ARD. The effects of different forms of T. erecta on the growth of apple seedlings, leaf photosynthesis, root antioxidant enzyme, soil enzymatic activity and microbial environment were investigated. Compared with the CK treatments, DS, FS, and IS treatments all significantly increased the biomass of apple seedlings and promoted root growth under replanting conditions. Among them, DS showed the best results. The activity of antioxidant enzyme including superoxide dismutase, peroxidase and catalase were significantly increased in roots grown in soils treated with T. erecta. Moreover, T. erecta treatment also increased the activity of soil urease, phosphatase, sucrase and catalase enzyme, significantly altered the abundance of soil fungal communities and, in particular, reduced the abundance of Fusarium oxysporum, the main causal fungus of ARD. Therefore, our results suggest that biofumigation of different forms of T. erecta enhanced the resistance of ARD by regulating root reactive oxygen levels and improving the soil fungal communities.

The gene family protein phosphatase 2C (PP2C) is related to developmental processes and stress responses in plants. Barley (Hordeum vulgare L.) is a popular cereal crop that is primarily utilized for human consumption and nutrition. However, there is little knowledge regarding the PP2C gene family in barley. In this study, a total of 1635 PP2C genes were identified in 20 barley pan-genome accessions. Then, chromosome localization, physical and chemical feature predictions and subcellular localization were systematically analyzed. One wild barley accession (B1K-04-12) and one cultivated barley (Morex) were chosen as representatives to further analyze and compare the differences in HvPP2Cs between wild and cultivated barley. Phylogenetic analysis showed that these HvPP2Cs were divided into 12 subgroups. Additionally, gene structure, conserved domain and motif, gene duplication event detection, interaction networks and gene expression profiles were analyzed in accessions Morex and B1K-04-12. In addition, qRT-PCR experiments in Morex indicated that seven HvMorexPP2C genes were involved in the response to aluminum and low pH stresses. Finally, a series of positively selected homologous genes were identified between wild accession B1K-04-12 and another 14 cultivated materials, indicating that these genes are important during barley domestication. This work provides a global overview of the putative physiological and biological functions of PP2C genes in barley. We provide a broad framework for understanding the domestication- and evolutionary-induced changes in PP2C genes between wild and cultivated barley.

In ancient villages, the spread of uninterrupted fires caused great damage to clustered wooden houses. Thus, the spread of fire among wooden houses should be systematically studied to explore its characteristics. Statistical analysis is a feasible way to study the characteristics and underlying mechanisms of fire in full-scale wooden houses. In this study, 4 full-scale wooden buildings were built in an ethnic village in Guizhou Province, and the fire spread test was conducted by igniting a 0.63-MW power wood crib. To investigate the fire spread, the visual characteristics were observed, and the temperatures and heat radiation at special locations were monitored with thermocouples and radiation flowmeters, respectively. The effect of relative slope, heat radiation, and wind direction on fire spread characteristics was established by mathematical statistics, and the measured temperatures were used to verify the statistics’ regularity. The results showed that in wooden houses, fire spread was mainly influenced by the slope, the distance between houses, and wind direction. When the inner wall of a wooden house is protected by a fireproof coating, the thermal radiation spread and fire spread are both slower. The slope and distance had the same influence weight (0.41) on fire spread; however, since they affect the process in different ways, they should be analyzed separately for fire risk evaluation. The findings of this study provide a theoretical foundation for understanding the fire spread process in wooden buildings.